Collapsing glomerulopathy (CG) is a common but poorly understood proliferative podocytopathies that portends rapid renal failure and refractoriness to empiric therapy. Clinical correlates suggest that CG results from the pathogenic interaction of intractable host susceptibilities and pro-inflammatory immune mediators. In this proposal, we seek to elucidate how immunocytoprotection of podocytes is lost and may be restored in hosts susceptible to CG. Towards this end, we have identified the interaction of TNF-a with TNF receptor 2 (TNFR2) on podocytes as a potential precipitant of CG. In turn, because podocytes harbor no known tolerance to inflammatory mediators, we have mapped the renal dendritic cell (DC) network to interrogate podocyte protection by Regulatory DCs. Our pre-clinical testing demonstrated prevention and reversal of CG by cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors (CGIs), broadly applicable new renal therapeutics discovered to induce potent, immunocytoprotective regulatory DCs. We therefore hypothesize here that regulatory DCs prevent TNFR2-mediated precipitation of CG, a therapeutic effect of CGIs, in the following three specific aims: 1) determine podocyte protection in TNFR2 null mice susceptible to CG;2) determine podocyte protection by regulatory DCs in TNFR2 competent mice susceptible to CG;and 3) validate pharmacologic immunocytoprotection in CG via indirubin CGIs. These studies will delineate immune mechanisms leading to the precipitation of and protection from CG, and identify new interventions for this devastating renal disease. PUBLIC HEALTH RELEVANCE: Collapsing glomerulopathy has emerged as an important cause of renal failure within the past three decades. The reasons for why patients can be afflicted with collapsing glomerulopathy are poorly understood, and, as a result, there are currently no effective therapies for this devastating renal disease. This R01 proposal seeks to better understand how activation of the immune system contributes to the development and progression of collapsing glomerulopathy and to design new therapeutic strategies based on this knowledge.